The relatively poor absorption of quaternary ammonium compounds from the lumen of the gastrointestinal tract, in effect, limits their utility in therapy. It is often required that a higher dose be given or alternative routes of administration sought. Of course, higher doses are almost always associated with undesirable side effects.
Trospium chloride is a quaternary ammonium compound that was introduced in to the market as a spasmolytic agent in 1967 (German patent 1 194 422). This active agent has been available as an orally administrable, solid administration form (tablets and dragees), for intravenous or intramuscular injection as an injection solution, and for rectal administration as suppositories, and is mainly used for the treatment of bladder dysfunctions (urge incontinence, detrusorhyperreflexia). Due to its permanent positive charge, and hence low permeability, its bioavailability is extremely low (only up to 10% in humans). The oral dosage form is given in a fairly high dose and thus is associated with the typical side effects for anticholinergics, such as heart rate increases, dryness of the mouth, accommodation difficulties, etc.
There have been various attempts to enhance the permeability and bioavailability of poorly absorbed drugs. Cavallito et al (U.S. Pat. No. 2,899,357) used pharmacologically inactive quaternary ammonium compounds to enhance the absorption of pharmacologically active quaternary ammonium compounds. The theory behind their invention is based on the following principle: absorption of quaternary ammonium compounds in the gastrointestinal tract appears to be low because such compounds bind tightly to anionic receptors in the wall of the tract and hence are not readily available for absorption. For example, mucin is composed chiefly of polysaccharides with acidic functional groups that retain quaternary ammonium compounds by ionic interaction. By using other pharmacologically inactive compounds, Cavallito thought it was possible to saturate these binding sites, thereby leaving fewer sites for the pharmacologically active compound to bind to. The problem with this approach is that many of the quaternary ammonium compounds that are available are pharmacologically active, not inactive. Also, a high level of an inactive quaternary ammonium salt is needed for it to be effective.
Schepky et al (U.S. Pat. No. 4,650,664) used organic acids and their derivatives to enhance the solubility of drugs such as mopidamol that are poorly soluble in basic media. Such acids, by lowering the pH of the microenvironment, improve the solubility of basic drugs. Mechanistically, this approach is not suitable for quaternary ammonium or otherwise permanently charged molecules, as they are highly soluble in aqueous media irrespective of the pH of the media. Stern et al (U.S. Pat. No. 6,086,918) disclosed a formula that enhances the absorption of peptides by protecting the peptides from the acid environment of the stomach and at the same time lowering the pH of the intestinal fluid and hence providing an environment that is less favorable to the activity of proteolytic enzymes. They used organic acids such as citric and tartaric acids as pH lowering agents in the small intestine.
Other approaches to enhance the bioavailability of poorly permeable drugs include the use of vasodilators such as nicotinic acid (U.S. Pat. No. 5,126,348), the use of polyglycerol esters of unsaturated fatty acids to enhance the solubility of actives (U.S. Pat. No. 4,650,664), the use of carnithine derivatives and cyclodextrins (EPO 119737), the use of complex carbohydrates to enhance the absorption of calcium and other minerals (U.S. Pat. No. 4,689,228), the use of surface active agents to enhance the bioavailability of drugs (U.S. Pat. Nos. 4,571,334, 4,334,934, and EPO 031603), and the pro-drug approach (U.S. Pat. Nos. 4,673,534, 4,443,435, 4,694,006, and EPO 036534).
There still remains an unmet need in the art to enhance the bioavailability of therapeutic quaternary ammonium compounds.